1. Field of the Invention
The invention is in the field of organic chemistry. The invention relates to a process for the synthesis of (3R,3′R)-zeaxanthin and (3R,3′S;meso)-zeaxanthin from a dehydration product of (3R,3′R,6′R)-lutein, namely, (3R)-3′,4′-didehydro-β,β-caroten-3-ol [(3R)-3′,4′-anhydrolutein]. The process involves regioselective hydroboration of (3R)-3′,4′-anhydrolutein to a mixture of (3R,3′R)-zeaxanthin and (3R,3′S;meso)-zeaxanthin followed by separation of these carotenoids by enzyme-mediated acylation.
2. Related Art
(3R,3′R,6′R)-Lutein and (3R,3′R)-zeaxanthin are two dietary carotenoids that are present in most fruits and vegetables commonly consumed in the US. These carotenoids accumulate in the human plasma, major organs, and ocular tissues [macula, retinal pigment epithelium (RPE), ciliary body, iris, lens]. In the past decade, numerous epidemiological and experimental studies have shown that dietary lutein and zeaxanthin play an important role in the prevention of age-related macular degeneration (AMD) that is the leading cause of blindness in the U.S. and Western World. Among the 7 stereoisomers of dietary (3R,3′R,6′R)-lutein, only (3R,3′S,6′R)-lutein (3′-epilutein) has been detected in the human plasma and tissues. There are also two stereoisomers of (3R,3′R)-zeaxanthin, these are: (3R,3′S;meso)-zeaxanthin and (3S,3′S)-zeaxanthin; these carotenoids are not of dietary origin. However, meso-zeaxanthin that is absent from human plasma, has been found in nearly all human ocular tissues. This carotenoid is presumably formed in the human eye tissues as a consequence of metabolic transformation of dietary (3R,3′R,6′R)-lutein (Khachik F. et al. J. Invest. Ophthalmol. Vis. Sci. 43, 3383-92, 2002). The chemical structures of these carotenoids are shown in Scheme 1. In view of the potential therapeutic application of dietary lutein, (3R,3′R)-zeaxanthin, and (3R,3′S;meso)-zeaxanthin, the industrial production of these carotenoids has received considerable attention. Due to its challenging total synthesis, dietary (3R,3′R,6′R)-lutein is isolated from saponified extracts of marigold flowers (Tagete erecta, variety orangade) and is commercially available as a nutritional supplement (Khachik, F. U.S. Pat. No. 5,382,714, Jan. 17, 1995).

Although dietary (3R,3′R)-zeaxanthin is very widely distributed in Nature, its concentration in most readily available natural products is not sufficiently high for commercial production by extraction and isolation. Contrary to the situation with (3R,3′R,6′R)-lutein, numerous lengthy multistep processes have been developed for the total synthesis of (3R,3′R)-zeaxanthin (Mayer, H. Pure Appl. Chem. 1979, 51, 535-564; Saucy, G. U.S. Pat. No. 4,153,615, May 8, 1979; Rüttimann, A., Mayer, H. Helv. Chim. Acta 1980, 63, 1456-1462; Müller, R. K. et al. Food Chem. 1980, 5, 15-45; Widmer, E. et al. Helv. Chim. Acta 1990, 73, 861-867).
There are also several processes that convert the commercially available (3R,3′R,6′R)-lutein or crude saponified extracts of marigold flowers by base-catalyzed isomerization to optically inactive (3R,3′S;meso)-zeaxanthin (Torres-Cardona, M. D.; Quiroga, J. U.S. Pat. No. 5,523,494, Jun. 4, 1996; Bernhard, K, Giger, A. U.S. Pat. No. 5,780,693, Jul. 14, 1998; Rodriguez, G. A. International Patent to Prodemex, WO 99/03830, Jan. 28, 1999). In another process, (3R,3′R,6′R)-lutein is transformed into (3R,3′S;meso)-zeaxanthin similar to the above methods and the latter is oxidized to β,β-carotene-3,3′-dione followed by reduction with sodium or potassium borohydride to give a racemic mixture of (3R,3′R)-zeaxanthin, (3S,3′S)-zeaxanthin, and (3R,3′S;meso)-zeaxanthin (Virgili, S. et al. International Patent to Investigaciones Quimicas Y Farmaceuticas, WO 97/31894, Sep. 4, 1997). However, due to the low overall yield and the fact that the racemic mixture of (3RS,3′RS)-zeaxanthin was not resolved, this approach does not provide an attractive route for the industrial production of these carotenoids.
To circumvent the problems associated with the poor yield and the control of the stereochemistry in transformation of (3R,3′R,6′R)-lutein to (3R,3′R)-zeaxanthin, an efficient process has been reported by the author (Khachik, F. U.S. Pat. No. 6,818,798 B1, Nov. 16, 2004; Khachik, F. J. Nat. Prod. 2003, 66, 67-72). According to this process, lutein was first converted to a diastereomeric mixture of (3R,3′R,6′R)-lutein and (3R,3′S,6′R)-lutein (3′-epilutein) by acid-catalyzed epimerization followed by separation of these carotenoids by enzyme-mediated acylation. The resulting 3′-epilutein was then converted to (3R,3′R)-zeaxanthin by base-catalyzed isomerization. This process provided a convenient and alternative route to the total synthesis of dietary zeaxanthin.
The author now wishes to report yet another alternative method for transformation of dietary lutein to (3R,3′R)-zeaxanthin and (3R,3′S;meso)-zeaxanthin. These carotenoids are initially prepared as a diastereomeric mixture that is subsequently separated into individual compounds with the aim to provide access to both of these important nutrients.